Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Toxicokinetic assessment using physico-chemical properties and toxicological study data.

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment using reliable physico-chemical properties and toxicological study data.

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

The toxicokinetic profile of Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol, a complex mixture of amides and salts, was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, and information gained from genotoxicity assays.

Test material

Test material information

Constituent 1

Reference substance name:

Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol

Molecular formula:

Too complex

IUPAC Name:

Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol

Test material form:

liquid

Details on test material:

- Appearance/ Physical State: light brown slightly viscous liquid
- Storage conditions: room temperature, in the dark

Specific details on test material used for the study:

The substance is a UVCB with an average molecular weight of 382.3. The substance is a light brown viscous liquid and is poorly water soluble. The water solubility was determined at a nominal loading rate of 0.01 g/L to be 2.73 x 10-4 g/L (positive mode) and 2.36 x 10-3 g/L (negative mode). The octanol/water partition coefficient is very high, in the range of log Pow 6.08 to 6.64 (which is >4, the bioaccumulation limit), and a low vapour pressure of 9.0 x 10-2 Pa @ 25°C. The surface tension of the substance determined to be 32.0 mN/m at 22.0 ± 0.5 °C. The substance is considered to be surface active and the critical micelle concentration is 3.1 x 10-2 g/L at 22.0 ± 0.5°C. The majority of the components of the substance are considered not to dissociate.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral Route
The physical chemical properties described above indicate that the majority of the components of the substance have an average molecular size within the range that may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested (<500). However, being highly lipophilic the substance may be expected not to easily cross gastrointestinal epithelial barriers. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats).

An acute oral gavage toxicity study identified no evidence of systemic toxicity at 2000 mg/kg bw. A repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of the substance or its metabolites.

Dermal Route
Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering both the average MW and the log Pow. Moreover, it is assumed that the dermal uptake of the substance is also limited because of its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at 2000 mg/kg bw. The substance is not classified as a skin irritant but modest levels of erythema and edema were observed in a skin irritation study, which suggests that some dermal absorption may be possible after prolonged contact.

Inhalation Route
The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a viscous liquid or gel), its’ low vapour pressure indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and based on the life-cycle information of this substance, is expected to be inconsequential.

Details on distribution in tissues:

Distribution
Systemic distribution of substance can be predicted from the physical chemical properties of this substance. The high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or another macromolecule. The lipophilic character of the substance, with high Log Pow, low water solubility and average MW of 382.3 suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the substance or its’ metabolites in body tissues.

Details on excretion:

The structural characteristics (amides) of the substance suggest that this it may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

Metabolite characterisation studies

Details on metabolites:

Metabolism
Like most xenobiotics, the substance may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacterial mutagenicity, mammalian cell mutagenicity, and a mammalian cell chromosomal aberration, in which the substance was subjected to rat hepatic microsomal enzyme systems, did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the substance was unchanged by the presence of the microsomal enzyme system.

Applicant's summary and conclusion

Conclusions:

Toxicokinetic assessment of ‘Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol’
 
The toxicokinetic profile of Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol, a complex mixture of amides and salts, was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, and information gained from genotoxicity assays.
 
Physico-chemical properties
 
The substance is a UVCB with an average molecular weight of 382.3. The substance is a light brown viscous liquid and is poorly water soluble. The water solubility was determined at a nominal loading rate of 0.01 g/L to be 2.73 x 10-4g/L (positive mode) and 2.36 x 10-3g/L (negative mode). The octanol/water partition coefficient is very high, in the range of log Pow6.08 to 6.64 (which is >4, the bioaccumulation limit), and a low vapour pressure of 9.0 x 10-2Pa @ 25oC. The surface tension of the substance determined to be 32.0 mN/m at 22.0±0.5°C. The substance is considered to be surface active and the critical micelle concentration is 3.1 x 10-2g/L at 22.0±0.5°C. The majority of the components of the substance are considered not to dissociate.
 
Absorption
 
Oral Route
The physical chemical properties described above indicate that the majority of the components of the substance have an average molecular size within the range that may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested (<500). However, being highly lipophilic the substance may be expected not to easily cross gastrointestinal epithelial barriers. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats).
 
An acute oral gavage toxicity study identified no evidence of systemic toxicity at 2000 mg/kg bw. A repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of the substance or its metabolites.
 
Dermal Route
Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering both the average MW and the log Pow. Moreover, it is assumed that the dermal uptake of the substance is also limited because of its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at 2000 mg/kg bw. The substance is not classified as a skin irritant but modest levels of erythema and edema were observed in a skin irritation study, which suggests that some dermal absorption may be possible after prolonged contact.
 
Inhalation Route
The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a viscous liquid or gel), its’ low vapour pressure indicate a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and based on the life-cycle information of this substance, is expected to be inconsequential.
 
Distribution
 
Systemic distribution of substance can be predicted from the physical chemical properties of this substance. The high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or another macromolecule. The lipophilic character of the substance, with high Log Pow, low water solubility and average MW of 382.3 suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the substance or its’ metabolites in body tissues.
 
Metabolism
 
Like most xenobiotics, the substance may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacterial mutagenicity, mammalian cell mutagenicity, and a mammalian cell chromosomal aberration, in which the substance was subjected to rat hepatic microsomal enzyme systems, did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the substance was unchanged by the presence of the microsomal enzyme system.
 
Excretion
 
The structural characteristics (amides) of the substance suggest that this it may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

Executive summary:

 Toxicokinetic assessment of ‘ Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol’ 

The toxicokinetic profile of Tall Oil Fatty Acids, compounds with 2-(2-aminoethoxy) ethanol, a complex mixture of amides and salts, was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, and information gained from genotoxicity assays.

 Physico-chemical properties

 The substance is a UVCB with an average molecular weight of 382.3. The substance is a light brown viscous liquid and is poorly water soluble. The water solubility was determined at a nominal loading rate of 0.01 g/L to be 2.73 x 10-4g/L (positive mode) and 2.36 x 10-3g/L (negative mode). The octanol/water partition coefficient is very high, in the range of log Pow6.08 to 6.64 (which is >4, the bioaccumulation limit), and a low vapour pressure of 9.0 x 10-2Pa @ 25oC. The surface tension of the substance determined to be 32.0 mN/m at 22.0±0.5°C. The substance is considered to be surface active and the critical micelle concentration is 3.1 x 10-2g/L at 22.0±0.5°C. The majority of the components of the substance are considered not to dissociate.

 

Absorption

 Oral Route

The physical chemical properties described above indicate that the majority of the components of the substance have an average molecular size within the range that may be expected to be absorbed within the mammalian gastrointestinal tract, should that material be ingested (<500). However, being highly lipophilic the substance may be expected not to easily cross gastrointestinal epithelial barriers. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats).

 

An acute oral gavage toxicity study identified no evidence of systemic toxicity at 2000 mg/kg bw. A repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of the substance or its metabolites.

 

Dermal Route

Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering both the average MW and the log Pow. Moreover, it is assumed that the dermal uptake of the substance is also limited because of its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at 2000 mg/kg bw. The substance is not classified as a skin irritant but modest levels of erythema and edema were observed in a skin irritation study, which suggests that some dermal absorption may be possible after prolonged contact.

 

Inhalation Route

The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a viscous liquid or gel), its’ low vapour pressure indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and based on the life-cycle information of this substance, is expected to be inconsequential.

 

Distribution

Systemic distribution of substance can be predicted from the physical chemical properties of this substance. The high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or another macromolecule. The lipophilic character of the substance, with high Log Pow, low water solubility and average MW of 382.3 suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the substance or its’ metabolites in body tissues.

 

Metabolism

 Like most xenobiotics, the substance may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacterial mutagenicity, mammalian cell mutagenicity, and a mammalian cell chromosomal aberration, in which the substance was subjected to rat hepatic microsomal enzyme systems, did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the substance was unchanged by the presence of the microsomal enzyme system.

 

Excretion

The structural characteristics (amides) of the substance suggest that this it may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.